| 1. |
- Jiang, Wangshu
(författare)
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Of spiders, bugs, and men : Structural and functional studies of proteins involved in assembly
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Protein assembly enables complex machineries while being economical with genetic information. However, protein assembly also constitutes a potential threat to the host, and needs to be carefully regulated.Sulfate is a common source of sulfur for cysteine synthesis in bacteria. A putative sulfate permease CysZ from Escherichia coli appears much larger than its apparent molecular mass when analyzed by chromatography and native gel. Clearly CysZ undergoes homo-oligomerization. Using isothermal titration calorimetry, we confirmed that CysZ binds to its putative substrate sulfate, and also sulfite with higher affinity. CysZ-mediated sulfate transport—in both E. coli whole cells and proteoliposomes—was inhibited in the presence of sulfite, indicating a feedback inhibition mechanism.Proteus mirabilis is a Gram-negative bacterium causing urinary tract infections. Its simultaneous expression of multiple fimbriae enables colonization and biofilm formation. Fimbriae are surface appendages assembled from protein subunits, with distal adhesins specifically recognizing host-cell receptors. We present the first three structures of P. mirabilis fimbrial adhesins. While UcaD and AtfE adopt the canonical immunoglobulin-like fold, MrpH has a previously unknown fold. The coordination of Zn or Cu ion by three conserved histidine residues in MrpH is required for MrpH-dependent biofilm formation.Spider silk is an assembly of large proteins called spidroins. The N-terminal domain (NT) of spidroins senses the pH decrease along the silk spinning gland, and transits from monomer to dimer. A locked NT dimer interlinks spidroin molecules into polymers. We identified a new asymmetric dimer form of NT by x-ray crystallography. With additional evidence from small angle x-ray scattering (SAXS), we propose the asymmetric dimer as a common intermediate of NT in silk formation.Alzheimer’s disease is a life-threatening dementia, where aggregation-prone Aβ peptides self-assemble into amyloid fibrils. Bri2 BRICHOS is a molecular chaperone that efficiently delays Aβ fibrillation, and protects the region of its pro-protein with high β-propensity from aggregation. Combining SAXS and microscale thermophoresis data, we confirmed binding between Bri2 BRICHOS and its native client peptide. Using site-directed mutagenesis, we showed that three conserved tyrosine residues in Bri2 BRICHOS are important for its anti-Aβ fibrillation activity.
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| 2. |
- Zhang, Tianfang
(författare)
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Probabilistic machine learning methods for automated radiation therapy treatment planning
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, different parts of an automated process for radiation therapy treatment planning are investigated from a mathematical and computational perspective. Whereas traditional inverse planning is labor-intensive, often comprising several reiterations between treatment planner and physician before a plan can be approved, much of recent research have been aimed at using a data-driven approach by learning from historically delivered plans. Such an automated planning pipeline is commonly divided into a first part of predicting achievable values of dose-related quantities, and a second part of finding instructions to the treatment machine mimicking as best as possible the predicted values. Challenges associated with this type of prediction–mimicking workflow exist, however—for example, in typical applications, patient data is high-dimensional, scarce and has relatively low signal-to-noise ratio due to inter-planner variations, and significant information may be lost in the transition between prediction and mimicking.We propose to address these challenges through better probabilistic modeling of the predictive inferences of dose-related quantities and increased accuracy of the optimization functions used for dose mimicking. In particular, starting with the disconnect between conventional planning objectives and evaluation metrics, in the first paper, we establish a framework for handling dose statistics as optimization function constituents. Subsequently, in the second and fourth papers, we present ways of predicting spatial dose and dose statistics, respectively, in a probabilistically rigorous fashion, the latter application relying on the similarity-based mixture-of-experts model developed in the third paper. As a nonparametric Bayesian regression model, equipped with a mean-field and stochastic variational inference algorithm, this mixture-of-experts model is suitable for managing complex input–output relationships and skewed or multimodal distributions. The second and fourth papers also introduce dose mimicking objectives able to leverage predictive distributions of spatial dose and dose statistics. In the fifth paper, we further build upon the probabilistic paradigm, merging the fields of multicriteria optimization and automated planning to create a semiautomatic alternative workflow in which certain manual intervention is possible. Lastly, in the sixth paper, we present a means of incorporating robustness against geometric uncertainties into an automated planning pipeline.
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| 3. |
- Walker, Anthony P., et al.
(författare)
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Integrating the evidence for a terrestrial carbon sink caused by increasing atmospheric CO2
- 2021
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Ingår i: New Phytologist. - : John Wiley & Sons. - 0028-646X .- 1469-8137. ; 229:5, s. 2413-2445
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric carbon dioxide concentration ([CO2]) is increasing, which increases leaf‐scale photosynthesis and intrinsic water‐use efficiency. These direct responses have the potential to increase plant growth, vegetation biomass, and soil organic matter; transferring carbon from the atmosphere into terrestrial ecosystems (a carbon sink). A substantial global terrestrial carbon sink would slow the rate of [CO2] increase and thus climate change. However, ecosystem CO2 responses are complex or confounded by concurrent changes in multiple agents of global change and evidence for a [CO2]‐driven terrestrial carbon sink can appear contradictory. Here we synthesize theory and broad, multidisciplinary evidence for the effects of increasing [CO2] (iCO2) on the global terrestrial carbon sink. Evidence suggests a substantial increase in global photosynthesis since pre‐industrial times. Established theory, supported by experiments, indicates that iCO2 is likely responsible for about half of the increase. Global carbon budgeting, atmospheric data, and forest inventories indicate a historical carbon sink, and these apparent iCO2 responses are high in comparison to experiments and predictions from theory. Plant mortality and soil carbon iCO2 responses are highly uncertain. In conclusion, a range of evidence supports a positive terrestrial carbon sink in response to iCO2, albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.
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